| The lack of selective damage cancer is one of the most important defects of anti-tumor drugs in clinical use.In order to improve the elective effect on tumor cells and reduce the side effects of drugs,the stragety of target drug design is provided.Therefore,the targeted drug delivery system based on endogenous molecules has become a hot research topic in the development of antitumor agents.Being high demand by tumor cells and high expression of PAT on cells membrane,polyamine is suitable for serving as the guiding carrier.The terminal alkyl polyamines can effectively reduce in vivo toxicity and improve the drug tolerance,more importantly,it can deliver the pharmacophore into tumor cells and increase the selective effects of anticancer drugs.Disulfide bond has several characteristics in employing as the linkage such as easy biodegradation,stable in physiological environment,responsive degrable to glutathione.Meanwhile,GSH is highly expressed in tumor cells,with the concentration can reach 1000 times higher than that in plasma.In this regard,using the disulfide bonds as a linkage would be beneficial for tumor-targeting and responsive release of antitumor drugs.Therefore,it is a new type of drug delivery system with multiple tumor targeting,and it can achieve the selectivity of anti-tumor drugs and reduce the toxicity.Based on the physiological characteristics of tumor cells,design an innovative multi-level target drug delivery system:would be proposed small molecular amine serving as a targeting carried that carry pharmacophore to the target site,disulfide linkage of different structure of responsiveness fracture would be responsible for releasing pharmacophore,and realizing multi-level targeted drug recognition.Thereby improving the selectivity and the efficacy,of antitumor drugs.In this thesis,the main contents and results are listed as follow:(1)Useing acridine as a model drug,the synthesized terminal alkyl of polyamines were conjugated together with disulfide bonds.A total of 13 target compounds,which were categorized as aliphatic and phenyl ring disulfide bond respectively,were synthesized.(2)In order to evaluate the process of durg transported into tumor cells and the ability of drug release,the model grugs were replaced by the fluorophores,fluorescein and coumarin,and were conjugate to different terminal alkyl polyamine by disulfide bonds.Therefore,9 reference compounds were synthesized.(3)Preliminary evaluation was implemented on both HepG2 cells and K562 cells.The resuls showed that compounds 19a-c were low toxic,and that the synthetic polyamine backbones in compounds 19a-c were superior to that in compounds 19d-g.In addition,the in vivo toxicity of some target compounds were also weak..(4)The in vitro stability and GSH responsive drug release ability were investigated through HPLC analysis.The results showed that compounds are stable in vitro environment(pH=7.4,37 ?),and disulfide bond can quickly disassemble in response to the high concentration of GSH,releasing the mother drug.(5)The process of compounds acrossing the membrane into tumor cells and release drug were studied by confocal microscopy.The results showed that the fluorescent reference compounds 35c and 35g could transport into HeLa cells,which indicated that the terminal alkyl of polyamine can transport drug into the tumor cells.Compounds 29a and 29b didn't have fluorescence in the absence of GSH,Upond the addition of GSH,HeLa cells were observed obvious blue fluorescence,which was attributed to that the alkylation polyamine-disulfide bond was responsed quickly to the high concentration of GSH and release drugs in cells. |
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